Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase

Abstract

Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active. eEF2K is regulated by various mechanisms, including phosphorylation through residues and autophosphorylation. Specifically, this protein kinase is downregulated through the phosphorylation of multiple sites via mTOR signaling and upregulated via the AMPK pathway. eEF2K plays important roles in numerous biological systems, including neurology, cardiology, myology, and immunology. This review provides further insights into the current roles of eEF2K and its potential to be explored as a therapeutic target for drug development.

Keywords: AMPK; cancer; drug development; eEF2K; immunometabolism; mTORC1; protein kinase; signaling pathways.

FIGURE 1

This schematic outlines the structure of eEF2K and the primary functional features of the molecule. It additionally depicts the direct (solid lines) and indirect (dashed lines) signaling pathways that moderate its activity. The end of the C-terminal, shown in purple, assists the catalytic domain, characterized in yellow, to phosphorylate eEF2. The phosphorylated residues shown in green indicate sites that activate eEF2K activity, and residues in red depict inhibited eEF2K sites. The auto-phosphorylated residues that trigger eEF2K are shown in orange. Sites shown in yellow represent residues that indirectly affect the phosphorylated sites near N-terminus, and gray residues are those that have known phosphorylation activity but do not affect eEF2K activity.

FIGURE 2

Outlined are the various pathways through which eEF2K is regulated and how it ultimately impacts protein synthesis. Solid lines depict direct pathways, and indirect pathways are shown with dashed lines. eEF2 is the only substrate for eEF2K, shown in the red box. ERK regulates eEF2K in two ways: 1) direct inhibition on eEF2K and 2) the induction of p90^RSK1. The regulation of STAT3 by eEF2K is under debate, but current evidence shows eEF2K inhibits STAT3 in lung cancer and activates it in liver cancer.

FIGURE 3

eEF2K plays a significant role in multiple pathologies. eEF2K is expressed at high levels in several diseases, including neurodegenerative diseases, cancer, cardiovascular disease, muscular hypertrophy, and other immune pathologies, causing it to serve as a suitable and promising drug target. eEF2K affects synaptic plasticity, memory function, and dendrite development in neurology. Dysfunction of these traits leads to the development and progression of neurodegenerative diseases. The progression of cancer and cancer-cell growth has also been correlated with eEF2K activity and expression levels.